The present invention concerns an apparatus and a method for liquid or solid state Nuclear Magnetic Resonance (NMR) spectroscopy and/or NMR imaging (MRI) of at least one animate or inanimate sample, which allows improving both the filling factor and the radio-frequency field amplitude in at least one detection coil surrounding said at least one sample.
A NMR apparatus contains in a statoric frame magnetic means, radio frequency (RF) means comprising excitation circuits, an emitting coil and RF receiving means. Located in a central hole of this statoric frame, this apparatus contains positioning means for holding the sample or an object to analyse. In some cases, especially in solid state NMR, the means for holding the sample have means for spinning it, and sometimes extra means for tilting the spinning axis. The spinning part is called the rotor. It has a cylindrical shape and wears at one end tiny turbo blades driven by air jets. The rotor is made of a material transparent for magnetic fields, generally made of ceramics. It may be filled with the sample to analyse, but when this sample is small, it wears an internal sample container, mechanically centred and whose axis is parallel to the mechanical axis of the rotor. The invention concerns small sized samples, so the rotor always contains a sample container whose diameter is smaller than the rotor diameter. It is necessary to underline that frequently, in NMR literature, the sample container is abusively called in short “sample” instead of “sample container”.
As known for many years, in NMR spectroscopy and/or imaging, the sample—be it an object or a subject—is placed inside a strong static and very homogeneous magnetic field B0. In a quantum description, nuclear spins (assuming that they have a quantum number I=½) can be parallel or anti-parallel with respect to the static magnetic field B0. Each of these two states has a different energy in the presence of B0. These energy levels are named Zeeman energy levels, and the spins can absorb energy in the radio-frequency range, to undergo transitions between their two states. In a classical description, the magnetic moments of the nuclear spins precess around the static magnetic field. The frequency ωL of the precession (called “Larmor precession”) is roughly proportional to the static magnetic field, also depending on the local chemical environment and can be used to probe molecular structure and dynamics. In order to absorb energy and induce transitions, an oscillating magnetic field B1 needs to be applied. This field is produced by antennas (i.e. coils) surrounding the object or subject. This field is oscillating at the Larmor frequency (resonance condition) and can be applied for time delays long enough to perturb the magnetization and rotate it at various angles. The typical NMR experiment consists of the application of this B1 field for a time delay τ, long enough to place the equilibrium magnetization M in the transverse plane xy. The length of this time delay is defined by the relation:γB1τ=π/2  (1)
where γ is the gyromagnetic ratio of the nucleus.
After application of this radiofrequency field (called π/2 pulse), the spins return to equilibrium. During this time, the magnetization still precesses around the static magnetic field and its trajectory is detected using antennas (i.e. tuned circuits) at the Larmor frequency.
Usually, the same antenna is used to perturb the nuclear magnetization (i.e. excitation) and then record (i.e. acquire) its response (namely free induction decay, also called “FID”) during its return to equilibrium. This signal contains the information about the frequencies of precession and a Fourier analysis of the FID gives the NMR spectrum. On the spectrum one can identify resonances based on their frequency differences.
One also records electronic noise in the signal coming from various sources such as the amplifiers, the preamplifier, the rest of the spectrometer together with thermal noise. Many scans of the signal are collected and summed coherently in order to improve the signal to noise (S/N) ratio on the spectrum.
The reciprocity theorem states that the signal coming from a small volume of sample dV detected by a coil is proportional to the strength of the radio-frequency field B1 that this coil can generate per unit current in the same point of space [1]. Thus, improved sensitivity can be obtained by rendering the strength of B1 field maximum for the volume of interest and this is typically performed by optimizing the filling factor of the coil. This filling factor may be defined as the ratio between the volume of the sample and the volume of the coil, which means that the best sensitivity is obtained for coil sizes comparable to the sample size.
On the other hand, the chemical environment manifests through various interactions, which are anisotropic (i.e. different interactions for different directions in space) and often lead to a continuous distribution of resonant frequencies. In liquids, the anisotropic parts of the interactions are averaged to zero due to free molecular tumbling and translation, thus the NMR spectra are narrow and the chemical information can be easily retrieved. However, in solids, the chemical shift anisotropy, the dipolar interactions, the quadrupolar interaction and sometimes the scalar couplings and the magnetic susceptibility broaden the spectrum and account for the loss in spectral resolution. One routinely used solution to improve resolution is the fast spinning of the sample around an axis making an angle, named magic angle, of approximately 54 degrees with the static magnetic field [2]. This technique, which is called “Magic Angle Sample Spinning” (MAS) is one of the cornerstones of high-resolution solid-state NMR, and most solid-state NMR probes are currently able to spin small sample holders (i.e. rotors) from 1000 Hz to 35000 Hz or even more. There have been methods of higher order averaging using simultaneous rotation, such as the method called “Double Rotation” (DOR, see [3]) or the sequential rotation method called “Double Angle Spinning” (DAS, see [4]) of the sample around two axis.
In all cases, RF antennas are fixed to the body of the probe or the stator, thus static, and placed outside of the sample holder leading to a poor filling factor and reduced sensitivity, especially for DOR experiments.
In liquid state NMR, liquid samples are studied using ordinary macroscopic size saddle type coils (i.e. macro-coils having a diameter ranging from 1 mm to 10 mm) or more recently micro solenoidal type coils have been designed to closely fit to horizontally disposed capillary tubes (100-1000 μm diameter), as shown in the drawings of [5-7] references. A drawback of these apparatuses is that they can only work with the coils being electrically connected and mechanically linked to the static part of the probe: this means that specific probes need to be constructed in each case.
In solid state NMR, static solid samples may be studied but most of the studies are performed under “Magic Angle sample Spinning” (MAS). Spinning allows for an averaging of the anisotropic interactions and thus for an improved spectral resolution. Very recently, micro-coils have been used in studies of static solid samples, improving upon sensitivity and B1 field strength [8]. In all modern setups, an antenna is used for excitation and detection, and it is static, being typically fixed on the body of the probe head with respect to the rotating sample.
Moreover, rotating small (sub-millimeter) objects very fast—typically at thousands of Hz—appears to be very difficult, because of mechanical constraints and demanding micro-machining. The sample holder needs to withstand high gas pressures and mechanical stress, and thus to have a non-negligible wall thickness. Common rotors have wall thicknesses ranging from about 0.5 mm to 0.75 mm, and scaling down to smaller sizes would compromise their mechanical stability. Machining hard materials with precision gets also very demanding for sub-millimeter sizes. Thus, it is very difficult to develop micro-rotors that rotate fast inside static RF micro-coils.
Various types of RF antennas have been used in the past in NMR and MRI. They generally comprise an electronic part consisting of the tuning and matching elements necessary to produce a tuned circuit and a coil close to, or inside which, the animate or inanimate sample under study is placed. This circuit can be tuned at the same time to many frequencies, allowing for multinuclear studies.
Inductive coupling between two circuits can be performed through physical proximity between them. The mutual inductance M between two coils is equal to the flux that crosses one coil when a current unity flows into the other one: it depends upon the geometrical characteristics of the coils and upon the distance between them. The coupling coefficient is defined as k=M/√(L1L2) where L1 and L2 are the inductances of the two coils. For a tuned secondary coil coupled to a primary coil, half of the total power dissipation occurs in the secondary when k=kc=1/√(Q1Q2), where Q1 and Q2 are the quality factors of the two coils.
In imaging such as in MRI, inductive coupling between two or more coils is commonly used in order to acquire images [9, 10], with the purpose to optimize the detection and the tuning bandwidth of the coil over a region of interest [11]. A secondary coil can be implanted [12] into the subject and allows for continuous monitoring. The sample under study, typically a patient, is static and motion can induce variations in the coupling between the primary and the secondary circuits, leading to signal and B1 amplitude variations. It is worth mentioning that in medical MRI the nature of the interactions is such that no spatial averaging is required by rotating the sample. The interactions are isotropic for MRI and thus no MAS technique is applied, leading to a completely different and independent development of the techniques than for NMR spectroscopy.
In NMR spectroscopy, however, inductive coupling has had much less success and it is essential to note here that it has only been used as a convenient way to match the impedance of the probe to the one of the generator. It has never been used in order to improve upon the filling factor in high-resolution NMR spectroscopy (high-resolution NMR meaning by usual definition a very specific NMR technique in which the strong magnetic field allows to detect small frequency shifts, such as a few Hz).
In spectroscopy, as explained above, one uses a detection coil that surrounds the sample under study in a way to provide a maximum filling factor and thus to optimize the sensitivity of detection for samples of standardized size. In solid state and liquid state NMR spectroscopy, the sample containers have standardized size that cannot suit to any sample, especially very small sized samples. Hence, using commercially available probes to study very small sized samples corresponds to a poor filling factor, resulting in a poor signal sensitivity.
In the particular case of samples of shielded radioactive materials, recent investigations are related by [13]: triple barrier containing rotors (of 7.5 mm outer diameter) were spun (at 3.5 kHz) and used to record 29Si spectra under MAS in ceramics containing 238Pu and 239Pu. One of the barrier was the rotor container itself, a second barrier of “Teflon” was used and a final barrier of “Shapal” was used to contain the radioactive material. However, as it is widely known, the existence of many protective layers reduces the sensitivity of detection. In common signal to noise formulas, the filling factor of the coil plays a very important role, since better sensitivity is achieved when the size of the coil is adapted to the size of the sample. If shielding barriers are needed, then the volume of the sample is reduced while the volume of a static coil remains the same, which drastically lessens the sensitivity.